Targeting ER Stress in TBI

描述（由申请人提供）：创伤性脑损伤（TBI）是退伍军人群体的主要健康问题。传统上，TBI诱导的脑损伤被认为仅限于创伤后的急性和亚急性期。然而，来自人类和实验研究的大量证据强烈表明，单一TBI可以引发进行性的长期神经退行性过程。然而，其基本机制尚未得到很好的理解。在TBI后的急性脑损伤中检测到内质网（ER）应激和异常蛋白积聚。这些变化可能导致脑损伤急性期神经元死亡。出乎意料的是，在我们的初步研究中，我们检测到延长的ER应激和未折叠蛋白反应（UPR）激活后3-21天的控制皮质撞击损伤。最重要的是，TBI后给予二十二碳六烯酸（DHA，22：6 n- 3）减弱了受损大鼠脑中的ER应激、异常蛋白质积累和泛素化蛋白聚集体形成。这些初步的发现使我们推测：1）TBI在伤后恢复阶段触发持续的ER应激和UPR激活：2）延长的ER应激、异常的蛋白积聚、泛素化蛋白聚集体形成和ER应激相关的炎症有助于TBI后神经功能缺损的发展; 3）DHA可以部分地通过减少ER应激和异常蛋白质积累来增强TBI后的长期神经功能恢复。这些假设将在三个具体目标中进行测试：目标1：确定TBI介导的慢性ER应激与TBI后异常蛋白质积累和聚集体形成之间的因果关系目标2：研究DHA介导的ER应激抑制是否导致TBI后异常蛋白质积累减少以及神经功能改善目标3：研究DHA对减少TBI后ER应激相关炎症的作用迄今为止，还没有有效的治疗方法被证明可以改善TBI后的长期神经功能恢复。DHA是一种营养补充剂，具有良好的安全性和多机制神经保护特性。本研究的目的是探讨一个新发现的功能， DHA在阻断TBI后持续性内质网应激、内质网应激相关炎症反应及改善远期神经功能方面的疗效。目前还没有临床试验研究DHA膳食补充剂对治疗或预防TBI的影响。这项研究的积极结果，以及其他临床前研究，将进一步保证 设计良好的临床试验，以确定补充ω-3多不饱和脂肪酸是否可以改善轻度脑外伤后的结果。

DESCRIPTION (provided by applicant): Traumatic brain injury (TBI) is a major health problem in the veteran population. Traditionally, TBI-induced brain damage is thought to be limited to the acute and sub-acute periods after trauma. However, abundant evidence from both human and experimental studies strongly suggests that a single TBI can trigger a progressive, long-term neurodegenerative process. However, the underlying mechanisms are not well understood. Endoplasmic reticulum (ER) stress and abnormal protein accumulation are detected in the acute brain injury following TBI. These changes may contribute to neuronal death in the acute stage of brain injury. Unexpectedly, in our pilot study, we detected prolonged ER stress and unfolded protein response (UPR) activation at 3-21 days after the controlled cortical impact injury. Most importantly, post-TBI administration of docosahexaenoic acid (DHA, 22:6n- 3) attenuated ER stress, abnormal protein accumulation, and ubiquitinated-protein aggregate formation in the injured rat brains. These preliminary findings led us to hypothesize that: 1) TBI triggers sustained ER stress and the UPR activation during the post-injury recovery phase; 2) the prolonged ER stress, abnormal protein accumulation, ubiquitinated-protein aggregate formation, and ER stress-associated inflammation contribute to development of neurological deficits after TBI; 3) DHA may enhance long- term neurological function recovery after TBI, in part, via reducing ER stress and abnormal protein accumulation. These hypotheses will be tested in three Specific Aims: Aim 1: To determine a causal link between TBI-mediated chronic ER stress and abnormal protein accumulation and aggregate formation following TBI Aim 2: To investigate whether DHA-mediated inhibition of ER stress leads to reduction of abnormal protein accumulation as well as improved neurological function after TBI Aim 3: To investigate effects of DHA on reduction of ER stress-associated inflammation after TBI To date, there are no effective treatments yet proven to improve the long-term neurological function recovery after TBI. DHA is a nutritional supplement with well-established safety profile and multi-mechanistic neuroprotective properties. The goal of this study is to investigate a newly discovered function of DHA in blocking sustained ER stress, and ER stress-associated inflammation after TBI and its efficacy in improving the long-term neurological function. There have been no clinical trials investigating the effects of DHA dietary supplementation on the treatment or prevention of TBI. A positive outcome from this study, together with other preclinical studies, will further warrant a well- designed clinical trial to determine whether omega-3 polyunsaturated fatty acid supplementation may improve outcomes following mild TBI.